Title : Crystal structures of native and
thrombin-complexed
heparin cofactor II reveal a multistep allosteric mechanism
Abstract :
- The serine proteases sequentially activated to form a fibrin clot are inhibited primarily by members of the serpin family, which use a unique beta-sheet expansion mechanism to trap and destroy their targets
- Since the discovery that serpins were a family of serine protease inhibitors there has been controversy as to the role of conformational change in their mechanism
- It now is clear that protease inhibition depends entirely on rapid serpin beta-sheet expansion after proteolytic attack
- The regulatory advantage afforded by the conformational mobility of serpins is demonstrated here by the structures of native and S195A thrombin-complexed heparin cofactor II ( HCII )
- HCII inhibits thrombin , the final protease of the coagulation cascade, in a glycosaminoglycan-dependent manner that involves the release of a sequestered hirudin-like N-terminal tail for interaction with thrombin
- The native structure of HCII resembles that of native antithrombin and suggests an alternative mechanism of allosteric activation, whereas the structure of the S195A thrombin- HCII complex defines the molecular basis of allostery
- Together, these structures reveal a multistep allosteric mechanism that relies on sequential contraction and expansion of the central beta-sheet of HCII